Autoantibodies to the insulin receptor occur in patients with insulin resistance as well as patients with hypoglycemia. We have carried out in vitro and in vivo studies of the effects of anti-receptor antibodies to mimic or antagonize insulin action. We are attempting to address the question of what determines the balance between the insulinomimetic and insulin antagonistic actions of anti-receptor antibody. In this regard, special attention is being paid to the ability of anti-receptor antibodies to accelerate the degradation of insulin receptors. Efforts are being made to develop monoclonal anti-receptor antibodies. These monoclonal antibodies will be useful in mapping the structural and functional domains of the insulin receptor molecule. We are studying the clinical aspects of the disease associated with autoantibodies to the insulin receptor. In addition to the abnormalities of carbohydrate metabolism, women with this syndrome have a tendency toward polycystic ovary disease, ovarian over-production of testosterone, and clinical evidence of masculinization.